Two independent pathways of regulated necrosis mediate ischemia–reperfusion injury

Abstract

Regulated necrosis (RN) may result from cyclophilin (Cyp)D-mediated mitochondrial permeability transition (MPT) and receptorinteracting protein kinase (RIPK)1-mediated necroptosis, but it is currently unclear whether there is one common pathway in which CypD and RIPK1 act in or whether separate RN pathways exist. Here, we demonstrate that necroptosis in ischemia-reperfusion injury (IRI) in mice occurs as primary organ damage, independent of the immune system, and that mice deficient for RIPK3, the essential downstream partner of RIPK1 in necroptosis, are protected from IRI. Protection of RIPK3-knockout mice was significantly stronger than of CypD-deficient mice. Mechanistically, in vivo analysis of cisplatin-induced acute kidney injury and hyperacute TNF-shock models in mice suggested the distinctness of CypD-mediated MPT from RIPK1/RIPK3-mediated necroptosis. We, therefore, generated CypD-RIPK3 double-deficient mice that are viable and fertile without an overt phenotype and that survived prolonged IRI, which was lethal to each single knockout. Combined application of the RIPK1 inhibitor necrostatin-1 and the MPT inhibitor sanglifehrin A confirmed the results with mutant mice. The data demonstrate the pathophysiological coexistence and corelevance of two separate pathways of RN in IRI and suggest that combination therapy targeting distinct RN pathways can be beneficial in the treatment of ischemic injury.RIP3 | RIP1 | programmed necrosis | apoptosis

Severe Pneumococcal Pneumonia Causes Acute Cardiac Toxicity and Subsequent Cardiac Remodeling

“…Pertinent to the present study, necroptosis has been recognized as a key cell death pathway in cardiomyocytes during ischemia-reperfusion injury and acute coronary syndromes (24)(25)(26).…”

“…Cardiomyocytes have been shown to die by apoptosis or necroptosis during injury or disease (24)(25)(26). Apoptosis is an immunoquiescent form of cell death that requires the activity of cysteine proteases known as caspases (42).…”

Synchronized renal tubular cell death involves ferroptosis

“…However, it was not ruled out that tubular cell death might have occurred secondary to some changes outside the tubular compartment: e.g., in RIPK3-dependent organ perfusion, which might be altered also upon Nec-1 treatment if the necroptotic pathway was involved. In fact, a discrepancy between the strong in vivo protection and the marginal protective effect of RIPK3-deficient freshly isolated tubules would be consistent with this hypothesis (4). A powerful approach to definitively study the involvement of cell-specific necroptosis is to delete components of the necroptosis-suppressing complex, which consists of FADD, caspase-8, RIPK1, and FLIP (26,27), and to analyze spontaneously occurring necroptosis.…”

Necroptosis is a key mediator of enterocytes loss in intestinal ischaemia/reperfusion injury

“…Necroptosis shares with necrosis the fact that dying cells display the morphological features of necrosis but not of apoptosis, but is highly regulated by an intracellular protein platform 14, 16. Recent advances have shown that activation of the kinase domain of receptor‐interacting protein1 (RIP1) and the assembly of RIP1/3‐containing signalling complex (termed the necrosome) mediated necroptosis contributes to the pathogenesis in preclinical models of brain 17, 18, heart 19, 20, and kidney 21, 22 I/R injury, which can be protected by using the RIP1 kinase inhibitor necrostatin (Nec)‐1. Meanwhile, the necrosome phosphorylates the mixed lineage kinase domain‐like protein (MLKL), which subsequently results in the rapid, active, and dynamic release of cell damage‐associated molecular patterns (DAMPs) following the loss of plasma membrane integrity and promotes ongoing inflammation and secondary tissue injury 23.…”